Significant progress has been made in the identification of host receptors for calciviruses (CVs) and rotaviruses (RVs). CVs recognize human histo-blood group antigens as receptors and different strains of CVs target different blood types. RVs utilize sialic residues and/or antigens on cell surface for attachment and/or penetration. Protective factors that block virus-host interactions have been identified in human milk, including homologs of cell surface glycoconjugate receptors, such as the Lewis and secretor antigens, and cell surface adhering molecules, such as lactadherin. Further studies to characterize these factors will facilitate development of strategies to control and prevent gastrointestinal tract infection and illness in children. This hypothesis will be addressed by the following specific aims. 1. Characterize the phenotypic expression of histo-blood group antigens in children that are associated with risk of calcivirus infection and relate this association to histo-blood group genotypes. 2. Characterize factors in human milk that block calcivirus binding to histo-blood group antigens and examine the association between concentration of such factors in human milk and prevention of childhood infection with calciviruses. 3. Isolate native lactadherin from human milk and determine the mechanisms by which this molecule protects infants from rotavirus infection. 4. Perform in vitro and in vivo experiments to test naturally occurring factors and synthetic compounds in preventing calcivirus and rotavirus binding to cell surface receptor(s). 5. Determine the relative contributions of antibody vs. non-antibody factors in human milk in protection in protection of infants from calcivirus and rotavirus infections.